01/09/18 - 9:45 AM to 11:00 AM
Department Seminar: Ambika Bhagi-Damodaran, Ph.D.
"Exploring enzymatic structure-function relations through protein design and small molecule discovery"
The three-dimensional structure of an enzyme determines its biological function and cellular interactions. Identification of vital structural features that control enzymatic functions are key to designing novel biocatalysts, imaging agents and drug leads. However, structural complexity associated with multiple domains, cofactors and/or membranous nature of certain enzymes have challenged such investigations. In this seminar, I will discuss the use of enzyme models and small molecule inhibitors as alternative pathways to probe and understand structure-function relations in complex enzyme systems. I will first discuss the use of myoglobin-based enzyme models to elucidate reaction mechanism of membranous heme-copper oxidase (HCO), the enzyme complex that catalyzes oxygen reduction during respiration. While these models mimic the active site of the protein, their structural simplicity as compared to native enzymes make them amenable to spectroscopic, computational and kinetic investigations. In turn, these studies answer several longstanding questions regarding the role of conserved amino acids, choice of metal and heme cofactors in HCOs and highlight the potential of protein engineering towards such endeavors. The second part of my talk will focus on understanding protein-protein interactions in p97, a multi-domain ATPase responsible for maintaining cellular protein quality control. Here, we utilize hit-to-lead optimized small molecule ligands to decipher the mechanism by which p97 is recruited in multi-cellular pathways. Structural, mechanistic and cellular characterization of these ligands reveal their conformationally-selective nature, and demonstrates how p97 employs conformational dynamics to modulate its protein interactions and biological function.
Event DetailsLocation: 331 Smith HallHost: Professor Lawrence Que Jr.Speakers:
- Ambika Bhagi-Damodaran, Ph.D.
- Department of Pharmaceutical Chemistry
- University of California, San Francisco